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PMID: 11153648 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Rod and cone visual cycle consequences of a null mutation in the 11-cis-retinol dehydrogenase gene in man.

Visual neuroscience ·Vol. 17 ·No. 5 ·2000-00-00 ·Pages 667-678

Cideciyan AV, Haeseleer F, Fariss RN, Aleman TS, Jang GF, Verlinde CLMJ, Marmor MF, Jacobson SG, Palczewski K

Abstract

Vertebrate vision starts with photoisomerization of the 11-cis-retinal chromophore to all-trans-retinal. Biosynthesis of 11-cis-retinal is required to maintain vision. A key enzyme catalyzing the oxidation of 11-cis-retinol is 11-cis-retinol dehydrogenase (11-cis-RDH), which is encoded by the RDH5 gene. 11-cis-RDH is expressed in the RPE and not in the neural retina. The consequences of a lack of 11-cis-RDH were studied in a family with fundus albipunctatus. We identified the causative novel RDH5 mutation, Arg157Trp, that replaces an amino acid residue conserved among short-chain alcohol dehydrogenases. Three-dimensional structure modeling and in vitro experiments suggested that this mutation destabilizes proper folding and inactivates the enzyme. Studies using RPE membranes indicated the existence of an alternative oxidizing system for the production of 11-cis-retinal. In vivo visual consequences of this null mutation showed complex kinetics of dark adaptation. Rod and cone resensitization was extremely delayed following full bleaches; unexpectedly, the rate of cone recovery was slower than rods. Cones showed a biphasic recovery with an initial rapid component and an elevated final threshold. Other unanticipated results included normal rod recovery following 0.5% bleach and abnormal recovery following bleaches in the 2-12% range. These intermediate bleaches showed rapid partial recovery of rods with transitory plateaux. Pathways in addition to 11-cis-RDH likely provide 11-cis-retinal for rods and cones and can maintain normal kinetics of visual recovery but only under certain constraints and less efficiently for cone than rod function.

MeSH Terms
Adaptation, Ocular/genetics Alcohol Oxidoreductases/chemistry,deficiency,genetics Amino Acid Sequence/genetics Antibody Specificity DNA Mutational Analysis Humans Kinetics Male Middle Aged Molecular Sequence Data Mutation/physiology NADP/metabolism Oxidation-Reduction Protein Folding Protein Structure, Tertiary/genetics Retinal Cone Photoreceptor Cells/enzymology,pathology,physiopathology Retinal Rod Photoreceptor Cells/enzymology,pathology,physiopathology Retinitis Pigmentosa/genetics,metabolism,physiopathology Vision, Ocular/genetics
Chemicals
NADP Alcohol Oxidoreductases retinol dehydrogenase
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Cideciyan Artur V
Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia.
Haeseleer Françoise
Department of Ophthalmology, University of Washington, Seattle.
Fariss Robert N
Department of Ophthalmology, University of Washington, Seattle.
Aleman Tomas S
Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia.
Jang Geeng-Fu
Department of Ophthalmology, University of Washington, Seattle.
Verlinde Christophe L M J
Biological Structure and BioMolecular Structure Center, University of Washington, Seattle.
Marmor Michael F
Department of Ophthalmology, Stanford University, Stanford.
Jacobson Samuel G
Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia.
Palczewski Krzysztof
Department of Ophthalmology, University of Washington, Seattle. | Department of Chemistry, University of Washington, Seattle. | Department of Pharmacology, University of Washington, Seattle.
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Article Info
Journal
Visual neuroscience
Abbr.
Vis Neurosci
ISSN
0952-5238
DOI
10.1017/s0952523800175029
Published
2000-00-00
Pages
667-678
Language
English
Region
England
NLM ID
8809466
PMCID
PMC1410813
Subset
IM
Grants
NEI NIH HHS · EY05627 · United States
NEI NIH HHS · F32 EY006935 · United States
NCRR NIH HHS · P51 RR000166 · United States
NEI NIH HHS · EY08061 · United States
NEI NIH HHS · R01 EY008061 · United States
NEI NIH HHS · EY06935 · United States
External Links
PubMed source DOI: 10.1017/s0952523800175029 PMC Full Text View journal details
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